N{40 -substituted n-arylsulfonyl ureas

ABSTRACT

N-arylsulfonyl-1,2,4,5-tetrahydro-3H-3-benzazepine-3carboxamides and addition salts thereof with bases, which compounds have useful hypoglycaemic action, as well as starting materials for their production; therapeutic compositions containing these carboxamides or their pharmaceutically acceptable addition salts and processes of producing hypoglycaemic effects in mammals. An illustrative embodiment is N-(p-tolylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3carboxamide.

United States Patent Dietrich Aug. 29, 1972 [54] N-SUBSTITUTEDN-ARYLSULFONYL [56] References Cited UREAS FOREIGN PATENTS ORAPPLICATIONS [72] gig" i 1,473,840 2/1967 France ..260/239 [73]Assignee: Ciba-Geigy Corporation Primary ExaminerAlton D. Rollins [22]Filed: July 16, 1970 Attorney-Karl F. Jorda and Martin J. Spellman [21]Appl. N0.: 62,756 [57] ABSTRACT R lated A 6 DataN-arylsulfonyl-l,2,4,5-tetrahydro-3H-3-benzazepinee U pp ca3-carboxamides and addition salts thereof with bases, DlVlSlOn 0f667,363, P 13, 1967, which compounds have useful hypoglycaemic action,Pat as well as starting materials for their production;

therapeutic compositions containing these carboxa- [52] US. Cl...260/239 BB, 260/239.6 mides or their pharmaceutically acceptableaddition [51] Int. Cl. ..C07d 41/08 salts and processes of producinghypoglycaemic ef- [58] Field of Search ..260/239 BB, 239.6 fects inmammals. An illustrative embodiment is N-(ptolylsulfonyl)-l,2,4,5-tetrahydro-3H-3-benzazepine-3- carboxamide.

3 Claims, No Drawings N-SUBSTITUTED N ARYLSULFONYL UREAS CROSS-REFERENCETO A RELATED APPLICATION This is a divisional of Ser. No. 667,363, filedSept. 13, 1967, now US. Pat. No. 3,575,962.

The invention relates to N'-substituted N-arylsulfonyl ureas havingvaluable pharmacological properties.

More particularly the invention pertains to N-arylsulfonyll,2,4,5-tetrahydro-3l-l-3-benzazepine-3-carboxamides and to additionsalts thereof with inorganic or organic bases. The invention is furtherconcerned with processes for the production of these carboxamides andthese addition salts and also comprehends tetrahydro-3H-3-benzazepinederivatives which are used as starting materials in said processes. Itis further an object of the invention to provide therapeuticcompositions consisting essentially of (l) a N-arylsulfonyll,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide according to theinvention, or a pharmaceutically acceptable addition salt thereof withan inorganic or organic base, and (2) a pharmaceutical carrier. Anotherobject of the invention is to provide processes of producinghypoglycaemic effects in mammals involving the administration to saidmammals of an effective amount of an inventive N-arylsulfonyl-l,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide, or a pharmaceuticallyacceptable addition salt thereof with an inorganic or organic base.

Compounds of the formula wherein R represents hydrogen, halogen up tothe atomic number 35, a lower alkyl, lower alkoxy, lower alkylthio,lower alkanoyl or amino group,

R represents hydrogen, or

R R represents the tetramethylene group,

and their addition salts with inorganic or organic bases, have not beenknown up to now.

In the compounds of formula I R may be in the o-, m or p-position andmay be exemplified for lower alkyl as e.g. methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec. butyl, tert. butyl, n-pentyl,isopentyl or 2,2-dimethyl-propyl; for lower alkoxy as e. g. methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec. butoxy, tert.butoxy, n-pentoxy, isopentoxy as well as 2,2-dimethylpropoxy; for loweralkylthio as e.g. methylthio, ethylthio, n-propylthio, isopropylthio,nbutylthio, isobutylthio, sec. butylthio, tert. butylthio, npentylthio,isopentylthio as well as 2,2dimethylpropylthio and, for lower alkanoyl,as e.g. acetyl, propionyl, Z-methyl-propionyl, butyryl, Z-methyl-butyrylas well as 3-methyl-butyryl.

The compounds of the above formula are produced according to theinvention by reacting an isocyanate derivative of the formula IItrimethylene or the wherein R represents hydrogen, halogen up to theatomic number 35, the amino group or a lower alkyl, lower alkoxy, loweralkythio or lower alkanoyl group, or it represents a group which can beconverted into an amino group by hydrolysis, reduction or reductivecleavage,

R represents hydrogen or R 'R represents the trimethylene ortetramethylene group, or a reactive functional derivative of a carbamicacid of the formula III R: OH

@ S 0gNC\ (111) wherein R R or R 'R have the meanings given in formula Ior II, with l,2,4,5-tetrahydro-3H-3- benzazepine [cf. P. RUGGLI et al.,Helv. Chim. Acta 18, 1388 (1935)], or with an alkali metalderivative ofthis compound, the reaction being performed, if desired, in the presenceof a condensing agent and, preferably, in an inert solvent, if necessaryhydrolysing or reducing the reaction product obtained to convert thegroup R into the free amino group and, if desired, converting thereaction product obtained into a salt with an inorganic or organic base.

As reactive functional derivatives of carbamic acids of the formula HI,e.g. their halides, particularly the chlorides, and their lower alkylesters, particularly the methyl or ethyl esters, also the phenyl estersare used. Also, amides, nitroamides, lower alkylamides, di (lower)alkylamides, diphenylamides, particularly N- methylamides,N,N-dimethylamides, in addition N- acylamides such as benzoylamides, and2-oxo derivatives of polymethyleneimides such as the 2-oxo-derivative ofpyrrolidinides, piperidides, hexamethyleneimides or octarnethyleneimidesare suitable.

As example of such functional derivatives of carbamic acids of theformula III can be mentioned: N-phenylsulfonyl carbamic acid chloride,methyl-, ethylor phenyl N-phenylsulfonyl carbamates, N-phenylsulfonylurea, N-nitro-N-phenylsulfonyl urea, N-methyl-N'- phenylsulfonyl urea,N,N-dimethyl-N-phenylsulfonyl urea, N,N-diphenyl-N'-phenylsulfonyl urea,N- benzoyl-N-phenylsulfonyl urea, N-phenylsulfonyl-2-oxo-pyrrolidine-l-carboxamide, N-phenylsulfonyl-2-oxo-piperidine-l-carboxamide, N-phenylsulfonyl-2-oxo-hexahydro-lH-azepine-l-carboxamide and N-phenylsulfonyl-2-oxo-octahydrolH-azeninel -ca.rboxamide, or derivativesof those compounds the groups R, or R R- of which at the benzene nucleusconform with the groups explicitly listed for R or R,R at the end offormula 1.

The reaction is performed, e.g. in the cold or by heating in an inertorganic solvent. Suitable inert organic solvents are, e.g. hydrocarbonssuch as benzene, toluene or xylene, ether-type liquids such as diethylether, dioxane or tetrahydrofuran, chlorinated hydrocarbons such asmethylene chloride and lower ketones such as acetone or methylethylketone.

The reaction of an isocyanate, carbamic acid ester or urea can beperformed in the absence of solvents or diluents. In general, nocondensing agent is necessary; if desired, however, an alkali alcoholatecan be used as such agent. Other condensing agents which can be used inthe reaction of an isocyanate are tertiary organic bases; isocyanates,however, can also be used in the form of an addition product with atertiary organic base.

The reaction of a carbamic acid halide with 1,2,4,5-tetrahydro-3l-l-3rbenzazepine is preferably performed according to theinvention in the presence of an acid binding agent. As such, inorganicbases or salts are used such as an alkali hydroxide, acetate, hydrogencarbonate, carbonate and phosphate, e.g. sodium hydroxide, sodiumacetate, sodium hydrogen carbonate, sodium carbonate and sodiumphosphate or the corresponding potassium compounds. In addition, calciumoxide, calcium carbonate as well as calcium phosphate and magnesiumcarbonate can also be used. Instead of inorganic bases or salts, alsoorganic bases are suitable, e.g. pyridine, trimethylamine ortriethylamine, N,N-di-isopropylamine, triethylamine or collidine. Usedin excess, these can also serve as solvents. For the reaction accordingto the invention with a carbamic acid chloride, instead of1,2,4,5-tetrahydro- 3H-3-benzazepine, an alkali metal derivative of thisbase such as a sodium, potassium, or lithium derivative can be used.

The conversion of a group R, of the reaction product into the free aminogroup which converts such product into a compound of formula I isperformed by hydrolysis, reduction or reductive cleavage depending onthe type of the group R Groups R, which can be converted into the freeamino group by hydrolysis are, e.g. acylamino, particularly loweralkamoylamino, groups such as the acetamido group or lower alkoxy orphenoxy carbonylamino groups such as the ethoxycarbonylamino orphenoxycarbonylamino group. Other examples are substitutedmethyleneamino groups such as the benzylideneamino orp-dimethylamino-benzylideneamino group. The hydrolysis to liberate theamino group can be performed, e.g. in acid medium such as by heating indilute methanolic hydrochloric acid, or, when R, is a lower alkoxy orphenoxy carbonylamino group, also under mild alkaline conditions, e. g.with IN to 2N sodium hydroxide solution, at room temperature.

An example of a group R, which can be converted by reduction into theamino group is the nitro group and examples of such groups which, byreductive cleavage, lead to the amino group are the phenylazo orp-dimethylamino-phenylazo groups. In general, these groups can bereduced catalytically, e.g. with hydrogen in the presence of Raneynickel, palladium or platinum charcoal, in an inert solvent such asethanol. In addition, other usual reduction processes can also be used,e.g. the reduction of nitro groups or the reductive cleavage of azogroups with the aid of iron in acetic or hydrochloric acid.

Compounds of the formula I are produced by a second process according tothe invention by reacting a reactive functional derivative oftetrahydro-3I-I-3- benzazepine-3-carboxylic acid with a sulfonamide ofthe formula IV benzazepine-B-carboxylic acid derivative with an alkalimetal derivative of a compound of formula IV, if necessary hydrolyzingor reducing the reaction product obtained to convert the group R, intothe free amino group and, if desired, converting the reaction productobtained into a salt with an inorganic or organic base.

The halides, particularly the chloride, are used as reactive functionalderivatives of tetrahydro-3H-3- benzazepine-3-carboxylic acid. Suitablealkali metal derivatives of sulfonamides of formula IV are, e.g. sodium,potassium or lithium derivatives.

The reaction of the halides according to the invention is preferablyperformed in an inert solvent in the presence of an acid binding agent.Suitable inert organic solvents are, e.g. hydrocarbons such as benzene,toluene or xylene, ethereal liquids such as diethyl ether, dioxane ortetrahydrofuran, chlorinated hydrocarbons such as methylene chloride andlower ketones such as acetone or methylethyl ketone. Inorganic bases orsalts are used as acid binding agents, e.g. an alkali hydroxide,acetate, hydrogen carbonate, carbonate and phosphate, such as sodiumhydroxide, sodium acetate, sodium hydrogen carbonate, sodium carbonateand sodium phosphate or the corresponding potassium compounds. Alsocalcium oxide, calcium carbonate and calcium phosphate and magnesiumcarbonate can be used. Instead of inorganic bases or salts, also organicbases are suitable, e.g. pyridine, trimethylamine or triethylamine,N,N-di-isopropylamine, triethylamine or collidine. Used in excess, thesecan also be used as solvents.

The subsequent conversion of a group R, in the reaction product into thefree amino group, which converts the reaction product into a compound offormula I is performed by hydrolysis, reduction or reductive cleavage asdescribed above depending on the type of the group RTetrahydro-BH-3-benzazepine-3-carbonyl chloride is an example of areactive functional derivative oftetrahydro-3H-3-benzazepine-3-carboxylic acid which. can be used asstarting material. This starting compound which is obtained, e.g. whentetrahydro-3I-I-3- benzazepine is reacted with phosgene in benzene, isnew and forms pan of the invention.

Compounds of formula I are produced by a third process according to theinvention by desulfurizing a thiourea derivative of the formula V (V)wherein R R or R R have the meanings given in formula I or II, ifnecessary, hydrolyzing or reducing the reaction product obtained toconvert the group R into the free amino group and, if desired,converting the reaction product obtained into a salt with an inorganicor organic base.

The desulfurization can be performed, e.g. with an oxidizing agent inacid, alkaline or neutral medium. Suitable oxidizing agents are, e.g.potassium ferricyanide, iron-HI-chloride, potassium permanganate,potassium chlorate, potassium hypochlorite or potassium hypoioditesolution. Hydrogen peroxide or sodium peroxide in alkaline solution,e.g. sodium hydroxide solution, are particularly advantageous oxidizingagents. In addition, heavy metal compounds such as mercury oxide or leadoxide can also be used for the desulfurisation. These metal oxides areadvantageously used in an aqueous organic solvent. Suitable organicsolvents are, e.g. lower alkanols such as methanol, alkane polyols suchas glycol or glycerine, ethereal liquids such as tetrahydrofuran ordioxan, ketones such as acetone or methylethyl ketone, carboxylic acidamides such as N,N-dimethylformamide and, also, urea derivatives such as1,1 ,3,3-tetramethyl-urea.

The subsequent conversion 'of a group R in the reaction product into thefree amino group which converts the product into a compound of formula Ican be performed as described at the end of the first process. Thehydrolysis of group R to the amino group there mentioned, however, canalso be performed simultaneously with the desulfurization.

Starting materials of the formula V are, e.g. those compounds thesubstituents R and R of which conform to the groups listed at the end offormulae I or II for R R or R R or R R or R 'R respectively. Thesestarting materials are new and form part of the invention. An example ofsuch a starting material is N- (p-tolylsulfonyl)-l,2,4,5-tetrahydro-3-H- 3- benzazepine3-3-thiocarboxamide which can beproduced, e.g. from p-tolylsulfonyl isothiocyanate andtetrahydro-3I-l-3-benzazepine in toluene. Other starting materials ofthis type can be produced analogously.

Compounds of the formula I according to the invention are produced by afourth process by hydrolyzing a compound of the formula VI wherein R ',Ror R R have the meaning given in formulae I or II and X represents ahalogen atom or a lower alkoxy or lower alkythio group, if necessaryreducing or further hydrolyzing the reaction product obtained to convertthe group R into the free amino group and, if desired, converting thereaction product obtained into a salt with an inorganic or organic base.

X as a halogen atom preferably represents the chlorine atom, as loweralkoxy or lower alkythio group it represents, e.g. the methoxy, ethoxyor the methylthio or ethylthio group.

When X is a halogen atom, the hydrolysis is advantageously performedwith the aid of an inorganic base, e.g. with sodium hydroxide, and whenX is a lower alkoxy or lower alkylthio group, instead of the inorganicbase, a halogen hydracid, e.g. hydrochloric acid is used. The reactionis advantageously performed in an organic solvent which is miscible withwater. Such solvents are, e.g. ketones such as acetone or methylethylketone, ether type liquids such as dioxane or tetrahydrofuran and alsocarboxylic acid amides such as N,N-dimethyl formamide.

The subsequent conversion of a group R in the reaction product into thefree amino group can be performed as described at the end of the firstprocess. If the substituent R, can be converted into the amino group byhydrolysis then this hydrolysis can be performed simultaneously to thereaction according to the invention.

Starting materials of formula VI are, e.g. those compounds thesubstituents R and R, of which conform to the groups listed followingformulas l or II for R R, or R,R or R R or R,'R respectively. Such agroup of starting materials are, e.g.N-phenylsulfonyltetrahydro-3H-3-benzazepine-3-carboximidoyl chloridessubstituted in the benzene ring by R and R These are obtained, e. g.from phosgene and correspondingly substitutedN-phenylsulfonyl-tetrahydro- 3I-I-3-benzazepine-3-thiocarboxamides,which are starting materials for the third process. The reaction can beperformed, e.g. in tetrahydrofuran. The reaction products can beconverted into another group of starting materials of the formula VIwherein the substituent X is a lower alkythio group if they are reacted,e. g. with the sodium salt of a lower alkane thiol such as methane POSOzN=C-N thiol. This second group of starting materials are N-phenylsulfonyl-tetrahydro-3H-3-benzazepine-3- thiocarboximido acid loweralkyl esters, e.g.N-phenylsulfonyl-tetrahydro-3H-3-benzazepine-3-thiocarboximido acidmethyl esters which are substituted in the benzene nuclei by the groupsR and R Corresponding N-phenylsulfonyl-tetrahydro-3I-I-3-benzazepine-3-carboximido acid lower alkyl esters compounds of formula VI wherein X isa lower alkoxy group obtained, e.g. by using a sodium salt of a loweralkanol as reaction component in the reaction instead of a sodium saltof a lower alkane thiol.

The same starting materials can also be produced starting fromtetrahydro-3I-l-3-benzazepine. This is converted with, e.g. cyanogenbromide, into tetrahydro-3I-I-3-benzazepine-3-carbonitrile which isconverted in a solution of hydrochloric acid in a lower alkanol into a2-lower alkyl-3-(tetrahydro-3H-3- benzazepin-3-yl)-pseudo urea. Thispseudo urea can be condensed, e.g. with a benzene sulfochloridesubstituted by the groups R, and R while splitting off hydrogenchloride.

The above described starting materials of formula VI are new and form apart of the invention.

As stated above, the invention also concerns the conversion of theN-arylsulfonyl-l,2,4,5-tetrahydro-3H-3- benzazepine-3-carboxamides intosalts with inorganic or organic bases. These salts have the samevaluable pharmacological properties as the free compounds of formula Iand can be prepared according to the usual methods well known in theart. Inorganic or organic bases such as alkali or alkaline earthhydroxides, carbonates or bicarbonates, triethanolamine, choline, N-dimethylor N -(B-phenylethyl)- biguanide, can be used for example forsalt formation.

The N-arylsulfonyl-1,2,4,5-tetrahydro-3H-3- benzazepine-3-carboxamide offormula I as well as their addition salts with inorganic or organicbases have now been found to unexpectedly exhibit valuablepharmaco'logical properties. On oral or parenteral administration theyshow hypoglycaemic action which characterizes them as suitable for thetreatment of diabetes.

Representative of these compounds are particularly N-phenylsulfonyl-l,2,4,5-tetrahydro-3H-3- benzazepine-3-carboxamide,

N-(p-toly1sulfonyl)- 1 ,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide, N-(p-chloro-phenylsulfonyl)- 1 ,2,4,5-tetrahydro-3II-3- benzazepine-3-carboxamide,N-(pfluoro-phenylsulfonyl)- l ,2,4,5-tetrahydro-3I-I- 3-benzazepine-B-carboxamide,

wherein R has the meaning as given in formula I for R as well as theaddition salts thereof with inorganic or organic bases.

The hypoglycaemic action of the compounds according to the invention mayillustratively be demonstrated e.g. by means of the following test:

The substance to be tested for hypoglycaemic action is suspended in tapwater with the aid of tragacanth and is administered by means of astomach sound. Five rats of an average weight of 190 g which have notbeen fed for 6% hours before the start of the test, and/or six rabbitsof an average weight of 2.5 kg. which have not been fed for 24 hoursbefore the start of the test, are used as test animals.

Blood samples are taken from the tail vein of the animals when usingrats in the test, and from the ear vein of the animals when usingrabbits, immediately before, and, in intervals, up to 24 hours after,administration of the test substance. The blood sugar is determinedaccording to HAGEDORN-JENSEN, Biochemische Zeitschrift 135, 46 1923 )7,and, with the autoanalyser, according to W. S. Hoffman, J. Biol. Chem.120, 51 (1937), respectively.

N-(p-tolylsulfonyl l ,2,4,5-tetrahydro-3H-3- benzazepine-B-carboxamideadministered in this test in amounts of from 20 to 100 mg/kg ofbodyweight in the rabbit causes a significant, long lasting reduction ofthe blood sugar.

On administration of 100 mg/kg of bodyweight, N-(pmethylthiophenylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide shows in this test a significant reduction ofthe blood sugar in the rat.

The compounds of the invention have a favorable therapeutic index, theirtoxicity is low: the LD of e.g. N-( p-chloro-phenylsulfonyl)-l,2,4,5-tetrahydro-3H-3- benzazepine-3-carboxamide in the mouse is 2400mg/kg p.o.

For their intended use the N-arylsulfonyl-l ,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamides of formula I as well as theirpharmaceutically acceptable addition salts with inorganic or organicbases are administered, preferably, orally in amounts depending on thespecies, age and weight of the subject under treatment; in general thedaily doses vary between about mg and about 2,000 mg.

For administration purposes, preferably, the above mentioned therapeuticcompositions are used. These compositions are presented for e.g. oraladministration in dosage units such as tablets, dragees (sugar coatedtablets), and the like.

Dosage units such as dragees (sugar coated tablets), tablets, preferablycontain 100-500 mg of an active substance according to the invention,i.e. 2080 percent of a compound of formula I. They are produced, e.g. bycombining the active substance with, e.g. solid pulverulent carrierssuch as lactose, saccharose, sorbitol, mannitol; starches such as potatostarch maize starch or amylopectin, also laminaria powder or citrus pulppowder; cellulose derivatives or gelatine, optionally with the additionof lubricants such as magnesium or calcium stearate or polyethyleneglycols of suitable molecular weights, to form tablets or dragee cores.The latter are coated, e.g. with concentrated sugar solutions which canalso contain, e.g. gum arabic, talcum and/0r titanium dioxide, or with alaquer dissolved in easily volatile organic solvents or mixture ofsolvents. Dyestuffs can be added to these coatings, e.g. to distinguishbetween varying dosages of active substance.

The following prescriptions further illustrate the production of tabletsand dragees:

a. 1,000 g of N-(p-tolylsulfonyl)1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide are mixed with 550 g of lactose and 292 gof potato starch, the mixture is moistened with an aqueous solution of8.0 g of gelatine and granulated through a sieve. After drying, 60.0 gof potato starch, 60.0 g of talcum 10.0 g magnesium stearate and 20.0 gof colloidal silicon dioxide are mixed in and the mixture is pressedinto 10,000 tablets each weighing 200 mg and containing 100 mg of activesubstance. If desired, the tablets can be grooved for better adaptationof the dosage.

b. A granulate is prepared from 1,000 g ofN-(pmethylthiophenylsulfonyl)-l ,2,4,5-tetrahydro-3H-3benzazepine-3-carboxamide, 379 g of lactose and the aqueous solution of6.0 g of gelatine. After drying, the granulate is mixed with 10.0 g ofcolloidal silicon dioxide, 40.0 g of talcum, 60.0 g of potato starch and5.0 g of magnesium stearate and the mixture is pressed into 10,000dragee cores. These are then coated with a concentrated syrup made from533.5 g of crystallized saccharose, 20.0 g of shellac, 75.0 g of gumarabic, 250 g of talcum, 20 g of colloidal silicon dioxide and 1.5 g ofdyestuff, and dried. The dragees obtained each weigh 240 mg and contain100 mg of active substance.

The following examples further illustrate the production of the newcompounds of formula I and of hitherto undescribed intermediateproducts, but they are by no means the only methods of producing same.The temperatures are given in degrees Centigrade. Percentages are givenby weight.

EXAMPLE 1 14.7 g of l,2,4,S-tetrahydro-3H-3-benzazepine (cf. P. Ruggliet al, Helv. Chim. Acta 18, 1388 (1935)) in 50 ml of anhydrous acetoneare added to 20 g of p-tolyl sulphonyl isocyanate in 150 ml of acetone.The crude product crystallises out of the reaction solution. Thesolution is diluted with 200 ml of water, the crystals are filtered offunder suction and taken up in 2N ammonia. An insoluble residue isfiltered off and the clear solution is added dropwise to 2N hydrochloricacid while stirring and cooling. The crude N-(p-tolylsulphonyl)- l,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide precipitates from thesolution. It is filtered off under suction, washed with water and driedin vacuo at 60 whereupon it melts at 158.5-l60. The substancecrystallises from a small amount of methanol and it decomposes at 10 1.The crystals contain methanol.

EXAMPLE 2 14.7 g of l,2,4,5-tetrahydro-3H-3-benzazepine are added to18.3 g of phenylsulphonyl isocyanate in 100 ml of anhydrous toluene. Anexothermic reaction occurs on completion of which the precipitatedcrystals are filtered off under suction and washed with petroleum ether.The crystals are dissolved in 150 ml of cold acetone and a small residueis removed from the solution by filtration. The filtrate is concentratedto half its volume and is diluted with water until it begins to goopaque. The precipitated crystalline end product is filtered off undersuction, washed with water and dried in vacuo at 60. TheN-phenylsulphonyl-l,2,4,5- tetrahydro-3H-3-benzazepine-3-carboxamideobtained melts at l761 79.

EXAMPLE 3 Starting from 14.7 g of 1,2,4,5-tetrahydro-3H-3- benzazepine,the following end products are obtained analogously to Example 2:

a. with 22 g of p-chlorophenylsulphonyl isocyanate,N-(p-chlorophenylsulphonyl)- l ,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide, M.P. l66.5168,

b. with 20.1 g of p-fluorophenylsulphonyl isocyanate, N-(p-fluorophenylsulphonyl)-l ,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide, M.P. l01l03, and

c. with 28.4 g of p-nitrophenylsulphonyl isocyanate, the newintermediate N-(p-nitrophenylsulphonyl)-l,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide,

EXAMPLE 5 The following end products are obtained analogously to example4 starting from 14.7 g of l,2,4,5-tetrahydro- 3H-3-benzazepine:

a. with 25.9 g of ethyl N-(p-methoxy-phenylsulphonyl)-carbamate,N-(p-methoxy-phenylsulphonyl- 1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide, M.P. 150-152, and

b. with 27.3 g of ethyl N-(p-ethoxy-phenylsulphonyl)-carbamate,N-(p-ethoxy-phenylsulphonyl)- 1 ,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide, M.P.

M.P. 203-208. This is hydrogenated in 300 ml of methanol and 4 g ofplatinum charcoal at room temperature and under normal pressure to formN-(pamino-phenylsulphonyl)-l ,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.

EXAMPLE 4 EXAMPLE 6 14.7 g of l,2,4,5-tetrahydro-3H-3-benzazepine and21.5 g of sulphanilyl urea are refluxed in 1,000 ml of dioxane, ammoniabeing developed. After 1 hour, the reaction mixture is concentrated and200 ml of water are added. The crystals obtained are dissolved in 2Nammonia. The filtered solution is acidified with 2N hydrochloric acidwhile stirring and cooling. The pure N-(p-amino-phenylsulphonyl l,2,4,5-tetrahydro-3H-3 -benzazepine-3-carboxamide is filtered off undersuction, washed with water and dried in vacuo at 60. It melts at182-183.

EXAMPLE 7 23 g of (p-methoxy-phenylsulphonyl)-urea and 14.7 g of1,2,4,5-tetrahydr0-3H-3-benzazepine in ml of anhydrous dioxane arerefluxed for 1 hour while stirring vigorously, ammonia being developed.After evaporating the reaction mixture in vacuo, the residue isrecrystallized from ethyl acetate. The N-(p-methoxyphenylsulphonyl )-l,2,4,5-tetrahydro-3H-3- benzazepine-3-carboxamide obtained melts at l50l5 2. According to its melting point and the melting point when mixedwith the compound obtained according to Example 5a., it is identicalwith that compound.

EXAMPLE 8 Starting from 14.7 g of l,2,4,5-tetrahydro-3H-3- benzazepine,the following end products are obtained analogously to Example 7:

a. with 24.4 g of (p-ethoxy-phenylsulphonyl)-urea,N-(p-ethoxyphenylsulphonyl)-l ,2,4,5 -tetrahydro-3H-3-benzazepine-3-carboxamide, M.P. 17l-l72. According to its melting pointand the melting point when mixed with the compound obtained according toExample Sb, it is identical with that compound;

b. with 24.2 g of (p-acetyl-phenylsulphonyl)-urea, N-(p-acetyl-phenylsulphonyl l ,2,4,5-tetrahydro-3H-3benzazepine-3-carboxamide;

c. with 21.8 g of (p-fluorophenylsulphonyl)-urea, N-(p-fluorophenylsulphonyl)- l ,2,4,5-tetrahydro-3H-3benzazepine-B-carboxamide. According to its melting point and themelting point when mixed with the compound obtained according to Example3b, it is identical with that compound;

d. with 23.7 g of (m-chlorophenylsulphonyl)-urea,N-(m-chlorophenylsulphonyl )-1 ,2,4,5 -tetrahydro-3H-3-benzazepine-3-carboxamide, M.P. 134-l 37;

e. with 24.6 g of (p-methylthio-phenylsulphonyl)- urea,N-(p-methylthio-phenylsulphonyl )-1 ,2,4 ,5-tetrahydro-3H-3-benzazepine-3-carboxamide, M.P. -150;

f. with 24 g of (indan-S-ylsulphonyl)-urea, N-(indan- S-yl-sulphonyD- 1,2,4,5-tetrahydro-3H-3-benzazepine- 3-carboxamide, and

g. with 21.4 g of (o-tolylsulphonyl)-urea, N-(o-tolylsulphonyl)- l,2,4,5-tetrahydro-3H-3-benzazepine-3- carboxamide, M.P. l69l 7 1.

EXAMPLE 9 15.3 g of 1,2,4,5-tetra.hydro-3H-3-benzazepine and 25.6 g of1-acetyl-3-(p-tolylsulphonyl )-urea are refluxed for 1 hour in 1,000 mlof anhydrous dioxane while stirring vigorously. The reaction mixture isthen concentrated, water is added, the crystalline crude product isfiltered off under suction and washed with water. The crude product isrecrystallized from ethyl acetate whereupon pureN-(p-tolylsulphonyD-l,2,4,5- tetrahydro-3H-3-benzazepine-3-carboxamideis obtained. According to its melting point and the melting point whenmixed with the compound obtained according to example 1, it is identicalwith that compound.

EXAMPLE 10 Starting from 14.7 .g of l,2,4,5-tetrahydro-3H-3-benzazepine, the following end products are obtained analogously toExample 9:

a. with 28.2 g of N(p-tolylsulphonyl)-2-oxo-pyrrolidine-l-carboxamide(M.P. l45-147) or with 29.6 g ofN-(p-tolylsulphonyl)-2-oxo-piperidine-l-carboxamide, (M.P. l06l07),N-(p-tolylsulphonyl)-l,2,4,5-tetrahydro-3l-l-3-benzazepine-3-carboxamide. According to its meltingpoint and the melting point when mixed with the compound obtainedaccording to Example 1, it is identical with that compound;

b. with 31.7 g of N-(p-chlorophenylsulphonyl)-2-oxo-piperidine-l-carboxamide (M.P. l38-140) or with 35.9 g ofN-(p-chlorophenylsulphonyl)-2-oxo-octahydro- 1 H-azoninel -carboxamide,N-( p-chlorophenylsulphonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide. According to its melting point and the melting point whenmixed with the compound obtained according to example 3 a), it isidentical with that compound, and

c. with 31.7 g of N-(p-chlorophenylsulphonyl)-2-oxo-hexahydro-lH-azepine-l-carboxamide (M.P. 120l21.5),N-(p-chlorophenylsulphonyl)- 1 ,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide, which is identical with thecompound obtained according to Example 10b).

EXAMPLE 11 a. 17.1 g of p-toluene sulphonamide are dissolved in 600 mlof dioxane and 5.6 g of pulverized potassium hydroxide are added. 21.0 gof tetrahydro-3H-3- benzazepine-3-carbonyl chloride are added dropwiseto the clear, hot solution and the whole is refluxed for 10 hours. Thereaction mixture is then concentrated in vacuo and 150 ml of 2Nhydrochloric acid are added. The crystals obtained are dissolved indilute ammonia, a sm l ount qianzgn s v d .SEPfiQPQ? is f s off and thefiltrate is again acidified with dilute hydrochloric acid. Theprecipitated crystals are, washed with water. After drying at 60 undervacuum, the pure N-(p-tolylsulphonyl)-tetrahydro-3H-3-benzazepine-3-carboxamide melts at l67.5l69 and is identical with the compoundobtained by Examples 1 or 4.

The starting material, tetrahydro-3H-3-benzazepine- 3-carbonyl chloride,is produced as follows:

b. 76,2g(0.5 mol) of tetrahydro-3H-3-benzazepine are dissolved in 200 mlof anhydrous benzene and then, at room temperature, phosgene isintroduced while stirring. The temperature rises to 60 and thetetrahydro- 3H-3-benzazepine hydrochloride crystallises out.Excess'phosgene is removed in a stream of nitrogen. Thetetrahydro-3H-3-benzazepine hydrochloride (M.P. 2l4-215) is thenfiltered ofi' and the residue is distilled. Thetetrahydro-3H-3-benzazepine-3-carbonyl chloride is used withoutpurification.

EXAMPLE 12 Starting from 21.0 g of tetrahydro3H-3-benzazepine-3-carbonyl chloride, the following end products are obtainedanalogously to Example 1 la:

a. with 19.4 g of p-chlorobenzene sulphonamide, N-(p-chloro-phenylsulphonyl)-tetrahydro-3H-3- benzazepine-3-carboxamide,M.P. l 66-168;

b. with 23.6 g of p-bromobenzene sulphonamide, N-(p-bromophenylsulphonyl)-tetrahydro-3H-3- benzazepine-3-carboxamide,

c. with 20.1 g of p-ethoxybenzene sulphonamide, N-(p-ethoxyphenylsulphonyl)-tetrahydro-3H-3- benzazepine-3-carboxamide,M.P. 17 l-172;

d. with 18.7 g of p-methoxybenzene sulphonamide,N-(p-methoxyphenylsulphonyl)-tetrahydro-3H-3- benzazepine-3-carboxamide,M.P. l50-152.

e. with 19.7 g of S-indane sulphonamide, N-(indan-S-ylsulphonyl)-tetrahydro-3H-3-benzazepine-3-carboxamide, and

f. with 17.5 g of p-fluorobenzene sulphonamide, N-(p-fluorophenylsulphonyl)-tetrahydro-3H-3- benzazepine-3-carboxamide,M.P. lOl-103.

EXAMPLE 13 a. 36.1 g of N-(p-tolylsulphonyl)tetrahydro-3H-3-benzazepine-3-thiocarboxamide are dissolved in ml of 2N sodium hydroxidesolution and 50 ml of 30 percent hydrogen peroxide are added dropwisewhile stirring. The reaction mixture is refluxed for 3 hours. Then,after cooling, it is acidified with 2N hydrochloric acid. The crudeproduct precipitates; it is filtered off and recrystallized from ethylacetate whereuponN-(ptolylsulphonyl)-tetrahydro-3H-3-benzazepine-3-carboxamide isobtained, M.P. l58-160.

b. The starting material, N-(p-tolylsulphonyl)-tetrahydro-SH-3-benzazepine-3-thiocarboxamide, is produced as follows:21.3 g of P-tolylsulphonyl isothiocyanate are added to 14.7 g oftetrahydro-3H-3- benzazepine in 50 ml of anhydrous toluene. Oncompletion of the strongly exothermic reaction, petroleum ether is addedto the reaction product until -it begins to turn opaque whereupon thesubstance crystallises. The pure N-(p-tolylsulphonyl)-tetrahydro-3H-3-benzazepine-3-thiocarboxamide melts at 129- 130, solidifies andmelts at 210.

EXAMPLE 14 a. 36.3 g of N-(p-tolylsulphonyl)-tetrahydro-3H-3-benzazepine-3-carboxirnidoyl chloride are dissolved in 200 ml ofdioxane, 200 ml of 2N sodium hydroxide are added and the whole is heatedfor 1 hour in a water bath. After cooling, the reaction mixture isacidified with 2N hydrochloric acid. The precipitated crystals arerecrystallized from ethyl acetate. The pureN-(ptolylsulphonyl)-tetrahydro-3H-3-benzazepine-3-carboxamide melts atl58l 60.

The starting material, N-(p-tolylsulphonyl)-tetrahydro-3H-3-benzazepine-3-carboximidoyl chloride, is produced asfollows:

B. Phosgene is introduced for 5 hours into a solution of 36.1 g ofN-(p-tolylsulphonyl)-tetrahydro-3H-3- benzazepine-3-thiocarboxamide in500 ml of anhydrous tetrahydrofuran. The reaction'is slightlyexothermic. Excess phosgene is then removed with nitrogen and thesolution is evaporated in vacuo. The residue is crystallized from ethylacetate whereupon pure N-(p-tolylsulphonyl)-tetrahydro-3H-3benzazepine-3-carboximidoyl chloride is obtained.

What is claimed is:

1. A compound of the formula wherein R" represents hydrogen, halogen upto the atomic numb0074lower alkylthio, lower alkanoyl, amino, loweralkanoylamino, lower alkoxycarbonylamino, phenoxycarbonylamino, ornitro,

R represents hydrogen, or

R,'R, represents trimethylene or tetramethylene,

and

X represents halogen, lower alkoxy or lower alkythio.

2. A compound as defined in claim 1 wherein X represents chlorine,methoxy, ethoxy, methylthio or ethylthio.

3. A compound as defined in claim 2 which is N-(ptolylsulfonyl)-l,2,4,5-tetrahydro-3H-3-benzazepine-3- carboximidoyl chloride.

Po-iow UNITED STATES PATENT OFFICE (5/69) CERTIFICATE OF CORRECTION P ntN 3, 7,934 Dated August 29, 1972 Inventor(s) HENRI DIETRICH It iscertified that error appears .in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column l L, line 3 should read number 35, lower alkyl, lower alkoxyg'lower al- Column 1, insert [30] A Foreign Application Priority Data"September 15, 1966 Switzerland.. .l3357/66 Signed and sealed this 9thday of April l9-7L (SEAL) Atte st:

EDWARD PLFLETCHERJR. C. MARSHALL DANN Attesting Officer Commissioner ofPatents

2. A compound as defined in claim 1 wherein X represents chlorine,methoxy, ethoxy, methylthio or ethylthio.
 3. A compound as defined inclaim 2 which isN-(p-tolylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboximidoylchloride.